Although advances in exogenous insulin therapy have enabled subjects with type 1 diabetes to adequately control their metabolic disturbances, there are still no treatment options that tackle its underlying cause. There is thus a need for improved treatments and options for prevention of type 1 diabetes.
IL-21 has a four helix bundle structure (helix 1-4/A-D—as defined e.g. in FIG. 1 in: J. Immunol., 2011 vol. 186 no. 2, p. 708-721), arranged in an up-up-down-down topology typical for the class I cytokines. IL-21 signals through a heterodimeric receptor complex, consisting of the private chain IL-21Rα (also referred to as IL-21R) and the γC/IL-2Rγ/common gamma chain the latter being shared by IL-2, IL-4, IL-7, IL-9, and IL-15. γC and IL-21Rα bind to non-overlapping binding sites on IL-21-IL-21Rα binds to helix 1+3 and γC binds to helix 2+4 on human IL-21. IL-21Rα binds IL-21 with high affinity and provides the majority of the binding energy. However, interaction with γC is required for signalling and IL-21 mutants which bind IL-21Rα but fail to interact properly with γC are potent antagonists of IL-21 signalling. IL-21 exerts pleiotropic effects on both innate and adaptive immune responses. It is mainly produced by activated CD4+ T cells, follicular T cells and Natural killer T cells. The amino acid sequence of human IL-21 is shown in SEQ ID NO 1. IL-21 antagonism has been suggested as a possible route for treatment of inflammation due to IL-21 multiple roles in stimulation of the immune system. Further details about IL-21/IL-21Rα binding are described in JBC, VOL. 287, NO. 12, pp. 9454-9460, Mar. 16, 2012 and examplatory anti-IL-21 antibodies are described in WO2010055366 and WO2012098113.
Glucagon-Like Peptide-1 (GLP-1) is a well-studied peptide for it's role in glucose metabolisme. The active forms of human GLP-1 is referred to as GLP-1(7-37) and GLP-1-(7-36)NH2 as the first 6 amino acid residues are removed during maturation. The peptide is very short lived and is a potent anti-hyperglycemic hormone capable of stimulating glucose-dependent insulin secretion and suppressing glucagon secretion. Therapeutic compounds for use in Type 2 diabetes treatment agonising the action of GLP-1 includes liraglutide, exenatide, lixisenatide, albiglutide and dulaglutide.